Small Molecule Inhibitors of Effector Th-17 Cells in Inflammatory Bowel Disease

炎症性肠病中效应 Th-17 细胞的小分子抑制剂

• 批准号: 7485537
• 负责人: Scott McNear Thacher
• 金额: $ 26.66万
• 依托单位: ORPHAGEN PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485537
• 关键词: Adverse effects; Agonist; Animal Model; Animals; Antigens; Autoimmune Diseases; Autoimmune Process; Bioavailable; Biochemical; Biological Assay; Biological Availability; Biopsy; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chemicals; Chromosome Mapping; Chronic; Class; Classification; Clinical; Colitis; Collaborations; Colon; Condition; Contractor; Crohn' s disease; Cultured Cells; Development; Disease; Drug Kinetics; End Point; Family; Genus Cola; Goals; Half-Life; Histology; Human; Immune; Immunity; Immunocompromised Host; Individual; Inflammatory; Inflammatory Bowel Diseases; Injectable; Interleukin-17; Intestinal Diseases; Intestines; Lead; Ligands; Literature; Mediating; Memory; Modeling; Modification; Monoclonal Antibodies; Mus; Neutrophil Infiltration; Nuclear; Nuclear Orphan Receptor; Nuclear Receptors; Oral; Orphan; Pathology; Pathway interactions; Patients; Peroxidase; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Positioning Attribute; Property; Public Health; Regulation; Reporting; Research; Retinoids; Role; Small Intestines; Steroids; Symptoms; T-Lymphocyte; Testing; Therapeutic; Thyroid Gland; Tissues; Ulcerative Colitis; Variant; Work; analog; antigen challenge; cytokine; design; experience; human disease; human study; in vivo; inhibitor/antagonist; interleukin-23; intestinal epithelium; medical schools; member; memory CD4 T lymphocyte; mouse model; neutrophil; novel; programs; receptor; scaffold; small molecule; transcription factor

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD), including Crohn's Disease and ulcerative colitis (UC), is a lifelong T cell- mediated inflammatory condition of the small intestine or colon. The highly proinflammatory cytokine interleukin-17 (IL-17) is elevated in proportion to disease activity in intestinal biopsies of both Crohn's and UC patients but is virtually absent in unaffected individuals. A new class of effector CD4+ T cells, known as Th-17 cells, has recently been identified that expresses IL-17 and several other inflammatory cytokines. The Th-17 cell is distinct from the better-studied Th1 and Th2 effector T cells and is the major T cell lineage implicated in animal models of colitis and other types of autoimmune disease. The applicants have identified structurally diverse small molecule antagonists to a previously unexplored orphan receptor that is required for CD4+ Th-17 cell differentiation. In cell culture, these receptor antagonists block Th-17 cell formation from na¿ve CD4+ T cells, inhibit the expansion of memory Th-17 cells following challenge by antigen, and suppress IL-17 release. These findings suggest that an orally bioavailable small molecule antagonist will have significant therapeutic potential in the treatment of IBD. This proposed new small molecule therapeutic class will also have significant therapeutic advantages--such as oral bioavailability and greater ease of administration--over injectable monoclonal antibodies to key cytokines in the Th-17 pathway such as IL-17 and IL-23. The specific aims of this proposal are to: (1) demonstrate that the novel receptor antagonists block IL-17 release in isolated intestinal tissue as expected if suppression of intestinal Th-17 is a target of the new compound class; (2) synthesize and characterize small molecule lead antagonists for in vivo studies from antagonists already identified at Orphagen; and (3) investigate lead antagonist suppression of disease activity in an established model of murine colitis that reflects Th-17 activity and is induced by transfer of na¿ve CD4+CD45RBhigh T cells to immunocompromised mice. Leads identified in this study will facilitate the identification of potential clinical candidates for treatment of IBD and other autoimmune indications in planned Phase II research. PUBLIC HEALTH RELEVANCE: Crohn's disease and ulcerative colitis are chronic, intestinal disorders for which treatment options are limited. The side effects of current medications are significant. We propose to characterize and develop a novel class of small molecule drugs that suppresses the formation and function of a novel lineage of T cells that appear to have a central role in the immune pathology of the disease.

描述（由适用提供）：炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎（UC），是小肠或结肠的终身T细胞介导的炎症状况。高度促炎的细胞因子白介素17（IL-17）与克罗恩和UC患者的肠活检中的疾病活性成比例升高，但在未受影响的个体中实际上不存在。最近已经鉴定出一种新型的效应CD4+ T细胞，称为Th-17细胞，该细胞表达了IL-17和其他几种炎性细胞因子。 TH-17细胞与研究的TH1和Th2效应T细胞不同，是结肠炎和其他类型的自身免疫性疾病的动物模型中隐含的主要T细胞谱系。申请人已将结构上的小分子拮抗剂鉴定为以前出乎意料的孤儿受体，这是CD4+ TH-17细胞分化所需的。在细胞培养中，这些受体拮抗剂从Na�VECD4+ T细胞中阻断了Th-17细胞的形成，抑制了抗原挑战后的记忆Th-17细胞的扩展，并抑制IL-17释放。这些发现表明，口服可生物可用的小分子拮抗剂将在治疗IBD方面具有显着的治疗潜力。该提出的新的小分子治疗类别还将具有明显的治疗优势 - 例如口服生物利用性和更便捷的给药性 - 对TH-17途径（例如IL-17和IL-23）中关键细胞因子的可注射单克隆抗体。该提案的具体目的是：（1）证明，如果抑制肠道TH-17是新化合物类别的目标，则新型受体拮抗剂阻止IL-17释放在分离的肠道组织中； （2）合成并表征小分子铅拮抗剂，用于从孤儿已经鉴定出的拮抗剂的体内研究； （3）研究铅拮抗疾病活性的铅拮抗剂在已建立的鼠类结肠炎模型中，该模型反映了TH-17活性，并通过将Na¿veCD4+CD45rbhigh T细胞转移到免疫功能低下的小鼠中引起。在这项研究中确定的铅将促进在计划的II期研究中鉴定潜在的IBD和其他自身免疫性适应症的潜在临床候选者。公共卫生相关性：克罗恩病和溃疡性结肠炎是慢性肠道疾病，治疗方案受到限制。当前药物的副作用很重要。我们建议表征和开发一类新型的小分子药物，这些药物抑制了T细胞的新型谱系的形成和功能，这些谱系在该疾病的免疫病理学中似乎具有中心作用。